Epigenetics and Nutrition: DNA Methylation, Dietary Intake and CVD

描述（由申请人提供）：人们普遍认为饮食和其他生活方式因素对心血管疾病的发病机制有重要作用，但对其中许多因素的确切机制仍知之甚少。表观遗传学是指不依赖于DNA序列变异的基因功能的可遗传变化，包括通过甲基化对DNA的共价修饰。表观遗传因素提供了一种可遗传的、可逆的和动态的机制来调节基因表达，以响应生活方式/环境（包括营养）诱导的外部刺激。在这项研究中，我们建议探讨发生在心血管疾病进展中的表观遗传变化，重点是饮食摄入量作为一个良好特征的老年人流行病学队列，心血管健康研究（CHS）的中介。具体来说，我们将研究：目的1：在老年人中，特定基因座的DNA甲基化是否与总死亡率，特别是心血管疾病死亡率的增加相关？目标2：特定基因座的DNA甲基化是否与心血管疾病，特别是心肌梗死、心绞痛、心力衰竭和中风的风险增加相关？目标3：在调整其他CVD风险因素（如高血压和糖尿病、亚临床疾病以及与CVD风险相关的行为/因素）之前和之后，DNA甲基化是否与饮食摄入相关？是关联独立的，还是甲基化似乎是沿着CVD的通路？目的4：饮食因素与心血管疾病患者和非心血管疾病患者的表观遗传漂变有何关系？饮食摄入量的变化是否与DNA甲基化的变化相对应？甲基化的改变是否介导了CVD的发生？我们将在500名CHS参与者的储存血液样本中测量30个预先选择的基因座中的DNA甲基化，这些基因座先前被证明与CVD疾病相关。为了测量表观遗传漂移，将对间隔6年采集的血液样本进行DNA甲基化分析，以与CHS临床评价期间给予的食物频率问卷相对应。疾病结局将包括总死亡率和心血管死亡率、心肌梗死事件、心绞痛、心力衰竭和卒中。要评估的饮食数据将包括估计的碳水化合物质量，包括血糖指数、血糖负荷和谷物纤维摄入量;膳食饱和脂肪、亚油酸和油酸（能量校正）;以及每周一次的全谷物、蔬菜、水果、肉类、金枪鱼/其他鱼类、炸鱼和酒精。将使用考克斯比例风险回归对CVD发病率和死亡率进行评估，并使用多元线性回归和降秩回归对膳食摄入的连续测量进行评估。模型将针对其他CVD风险因素进行调整，以评估饮食在表观遗传漂变和CVD中的作用。结果将导致更好地理解控制表观基因组变异的机制，从而识别可能最终成为新型治疗目标的关键疾病相关改变。

DESCRIPTION (provided by applicant): It is widely accepted that diet and other lifestyle factors contribute significantly to the pathogenesis of cardiovascular disease, however the precise mechanisms for many of these factors remains poorly understood. Epigenetics refers to heritable changes in gene function that are not dependent on DNA sequence variation and includes the covalent modification of the DNA by methylation. Epigenetic factors provide a heritable, reversible and dynamic mechanism for regulating gene expression in response to the external stimuli induced by lifestyle/environment including nutrition. In this study we propose to explore epigenetic changes that occur in the progression to cardiovascular disease with a focus on dietary intake as the mediator in a well-characterized epidemiologic cohort of older adults, the Cardiovascular Health Study (CHS). Specifically, we will investigate: AIM 1: Is DNA methylation of specific loci associated with an increased risk of total mortality and, specifically, cardiovascular disease mortality, in older adults? AIM 2: Is DNA methylation of specific loci associated with an increased risk of incident cardiovascular disease, specifically myocardial infarction, angina pectoris, heart failure, and stroke? AIM 3: Is DNA methylation related to dietary intake prior to and after adjustment for other CVD risk factors such as hypertension and diabetes, subclinical disease, and behaviors/factors related to CVD risk? Are association independent or does methylation appears to be along the pathway to CVD? AIM 4: How are dietary factors related to epigenetic drift in persons with and without CVD? Does change in dietary intake correspond with change in DNA methylation? Does change in methylation mediate the association with CVD? We will measure DNA methylation in 30 pre-selected loci previously demonstrated to be related to CVD disease in stored blood samples of 500 CHS participants. To measure epigenetic drift, DNA methylation will be analyzed on blood samples taken 6 years apart to correspond with the food frequency questionnaires administered during CHS clinical evaluations. Disease outcomes will include total and cardiovascular mortality, incident myocardial infarction, angina pectoris, heart failure and stroke. Dietary data to be assessed will include estimated carbohydrate quality, including glycemix index, glycemic load, and cereal fiber intake; dietary saturated fat, linoleic acid, and oleic acid (energy-corrected); and weekly servings of whole grains, vegetables, fruits, meats, tuna/other fish, fried fish, and alcohol. Associations will be evaluated using Cox proportional hazards regression for incidence of CVD and mortality, and multiple linear regression and reduced rank regression for continuous measures of dietary intake. Models will be adjusted for other CVD risk factors to assess the role of diet in epigenetic drift and CVD. Results will lead to a better understanding of mechanisms controlling epigenomic variation allowing for identification of crucial disease-related alterations that may ultimately be targeted for novel treatment.